Project Abstract Understanding the influence of the neural efferent and afferent regulation of ?-cell health and function would be an important advancement. Although it is known that neural input plays a critical role in the health of the pancreas, details of the neuroanatomy and neurobiology of the human pancreas remains largely unexplored. It may be that T1D patients, wherein residual ?-cells continue to secrete C-peptide, could benefit from neuromodulation therapies that stimulate neurovascular regrowth and result in anti-inflammatory effects in the pancreas. Furthermore, neuromodulation therapies may help to improve insulin secretion in patients with T2D or perhaps delay onset of disease for those at high risk for T1D (e.g. first-degree relative with T1D, multiple islet autoantibodies, genetic risk factors). Both knowledge of the functional neuroanatomy and enabling technologies to test this hypothesis do not currently exist. This project brings together a potent combination of experts in islet biology, neurophysiology, bioengineering, and clinical endocrinology with an innovative approach to define the comparative neuroanatomy of the human and rat pancreatic neural network. Our hypothesis is that pancreatic ?-cells, functioning like peripheral neurons, maintain blood glucose levels, in part, due to the neural regulation of islet blood flow. This novel hypothesis will be tested by one specific aim: 1) To determine pancreatic neuroanatomy. These studies will enable understanding and mapping of the autonomic and sensory efferent and afferent networks in normal human and rat pancreas. Importantly, our studies will map the human pancreatic neural networks utilizing specimens already collected from human organ donors without diabetes and those with T1D or T2D using optical clearing methodologies and high resolution 3D microscopy. The outcomes of these studies will provide critical design data for logical application of next-generation neuromodulation technologies to improve islet health. This proposed work is directly in-line with the SPARC program to understand comparative neuroanatomy of the endocrine pancreas to enable neuromodulation strategies for amelioration of end organ diseases.